WELCOME & INTRODUCTIONS · •Formulate individualized treatment plans for patients with IBS...

Irritable Bowel Syndrome and Chronic Constipation: Digesting Recent Advances and Current Thinking

© 2013 Paradigm Medical Communications, LLC, except where noted. 1

© 2013 Paradigm Medical Communications, LLC, except where noted. Content may not be reproduced in whole or in part without the express written consent of Paradigm Medical Communications, LLC.

WELCOME & INTRODUCTIONS

William D. Chey, MD



Housekeeping

• There will be a Q&A session at the end of the program; if you would like to pose a question to the faculty, please write it on one of the cards on your table

• Please silence your cell phones and pagers

Agenda

Incidence and Impact of IBS (subtypes) and CC William D. Chey (Chair)

Managing IBS-D: Evidence-Based Strategies for Diagnosis and Treatment Darren M. Brenner

The Diagnostic Dilemma of IBS-C and CC Brian Lacy

Nuanced Treatment of IBS-C and CC Amy E. Foxx-Orenstein

Shared Decision Making to Improve Care All Faculty



Faculty

William D. Chey, MD (Chair) Professor of Medicine Director , GI Physiology Laboratory Co-director, Michigan Bowel Control

Program University of Michigan Health System Ann Arbor, MI Darren M. Brenner, MD Assistant Professor of Medicine and

Surgery Northwestern University Feinberg

School of Medicine Chicago, IL

Amy E. Foxx-Orenstein, DO, FACG, FACP Associate Professor of Medicine Director of Motility Director of Constipation and Pelvic Floor Clinic College of Medicine Mayo Clinic Consultant Division of Gastroenterology Department of Internal Medicine Mayo Clinic Scottsdale, AZ Brian E. Lacy, MD, PhD Professor of Medicine Division of Gastroenterology and Hepatology Dartmouth-Hitchcock Medical Center Lebanon, NH

Disclosures

William D. Chey, MD (Chair) Retained Consultant: AstraZeneca Pharmaceuticals LP; Forest Laboratories, Inc; GlaxoSmithKline; Ironwood Pharmaceuticals; Prometheus Laboratories Inc.; Perrigo Company; Purdue Pharma; Salix Pharmaceuticals, Inc.; Sandhill Scientific; Takeda Pharmaceutical Company Limited

Darren M. Brenner, MD Advisory Board: Perrigo Company; Salix Pharmaceuticals, Inc. Speakers Bureau: Forest Laboratories, Inc.; Ironwood Pharmaceuticals; Salix Pharmaceuticals, Inc.

Amy E. Foxx-Orenstein, DO, FACG, FACP Retained Consultant: Forest Laboratories, Inc.; Ironwood Pharmaceuticals Speakers Bureau: Salix Pharmaceuticals, Inc

Brian Lacy, MD, PhD Retained Consultant: Ironwood Pharmaceuticals; Takeda Pharmaceutical Company Limited

Paradigm Medical Communications, LLC staff members: no financial conflicts to disclose.

Independent peer-reviewer of this activity: no financial conflicts to disclose.



Commercial Support

This CME initiative is supported by an educational grant from Forest Research

Institute, a subsidiary of Forest Laboratories, Inc., and Ironwood Pharmaceuticals.

Continuing Medical Education (CME) Information

Educational Objectives Upon proper completion of this activity, participants should be better able to:

• Describe current evidence-based approaches to accurately characterize IBS (subtypes) and CC in order to differentiate them from other medical conditions that present with similar symptoms.

• Formulate individualized treatment plans for patients with IBS (subtypes) and CC based on unique patient characteristics and understanding of current clinical evidence.

• Describe strategies for improving communication and increasing a coordinated approach for care of patients with IBS (subtypes) and CC among a multidisciplinary team of physicians and allied healthcare professionals.



• Each question will be displayed on a slide with an ORANGE title.

• To enter a response, press the button representing your choice when the countdown timer appears.

• You will have 6 seconds to enter a response.

• If you change your mind, just press the new button. The computer will only accept the last response.

• Following the countdown, a graph will appear displaying the distribution of responses.

Using the Audience Response Pads

ARS

INCIDENCE AND IMPACT OF IBS (SUBTYPES) AND CC

William D. Chey, MD



IBS (subtypes) & CC are Common

IBS CC

≈25-45 million people • 10%-15% of US population1

≈63 million people • ≈20% of US population2

Demographics3,4

• All ages (most common <50 y) • Peak incidence early adult to 34 y • Female > male

Demographics

• Elderly (≈40% ≥65 y)5

• Female > male6

Up to 3.5 million physician visits/y7 ≈2.5 million physician visits/y8

1. IFFGD. www.aboutibs.org/site/about-ibs/facts-about-ibs/. Accessed 8/23/13. 2. Higgins PD et al. Am J Gastroenterol. 2004;99:750-759. 3. Agarwal N et al. Gastroenterol Clin N Am. 2011;40:11-19. 4. Pimentel M. Gastroenterol Hepatol (NY). 2010;6(7):1-15. 5. Harris LA. www.medscape.org/viewarticle/544467_2.Accessed 3/26/13. 6. Suares NC et al. Am J Gastroenterol. 2011;106:1582-1591. 7. Black TP et al. J Gastrointestin Liver Dis. 2012;21(2):153-156. 8. Arora G et al. PLoS ONE. 2012;7(10):e42910.

CC, chronic constipation; IBS, irritable bowel syndrome

11

IBS & CC are Costly

Direct Cost of IBS

• Annual cost per patient: $50491

• 50% higher costs vs matched controls2

Indirect Cost of IBS1

• Absenteeism • Impaired productivity

Direct Cost of CC • Annual cost per patient: $75221

• >2x cost of controls over 15-y period2

Indirect Cost of CC3-5

• Compared with matched controls, those with CC report – Significantly reduced HRQoL and

work productivity

– Significantly greater use of healthcare resources (office and ED visits, hospitalizations)

– More missed workdays

12

1. Lacy BE et al. Therap Adv Gastroenterol. 2012;5(4):233-247. 2. Agarwal N et al. Gastroenterol Clin North Am. 2011;11-19. 3. Choung RS et al. Aliment Pharmacol Ther. 2011;33:251-260. 4. Arora G et al. PLoS ONE. 2012;7(10):e42910. 5. Sun SX et al. Dig Dis Sci. 2011;56(9):2688-2695

ED, emergency department; HRQoL, health-related quality of life



The Patient-Physician Encounter: Patient Perspective

• Embarrassing symptoms

– Significant interference with daily life

• Perceived lack of validation, empathy, and understanding of the nature of symptoms

– Clinicians may underestimate symptom occurrence, severity, and impact on QoL

• Minimization/dismissal of symptoms – “Don't worry, it's nothing serious”

– “It’s a nuisance, but it won’t kill you”

– “You’ll have to learn to live with it”

– “It's all in your head”

IBS Patients: Their Illness Experience and Unmet Needs. www.aboutibs.org/pdfs/IBSpatients.pdf. Accessed 8/23/13. McCormick JB et al. Health Qual Life Outcomes. 2012;10(1):25. 3. 13

The Patient-Physician Encounter: Physician Perspective

• No reliable biomarker or universal pathophysiology1

• Diverse symptoms (GI and non-GI) frequently complicated by psychosocial comorbidities1 – Difficult to quantify objectively

• Many organic conditions can masquerade as IBS or CC1,2

• Treatments offer marginal therapeutic gain and can cause potential harms

1. Camilleri M. Ther Adv Gastroenterol. 2012;5(6):381-386. 2. Mearin F, Lacy BE. Neurogastroenterol Motil. 2012;24(9):791-801. 14

GI, gastrointestinal



Key Takeaways

• IBS and CC are

– Common

– Costly

– Significant

• IBS and CC have overlapping symptoms that can cause challenges for patients and providers

• A trusting patient-provider relationship and evidence-based management recommendations can improve outcomes

15

MANAGING IBS-D: EVIDENCE-BASED STRATEGIES FOR DIAGNOSIS AND TREATMENT

Darren M. Brenner, MD



Rome III Diagnostic Criterion for IBS*

• Recurrent abdominal pain or discomfort† ≥3 d/mo in the last 3 mo associated with ≥2 of the following: – Improvement with defecation

– Onset associated with a change in frequency of stool

– Onset associated with a change in form (appearance) of stool

*Criterion fulfilled for ≥3 mo with symptom onset ≥6 mo prior to diagnosis †Discomfort means an uncomfortable sensation not described as pain

Rome Organization. www.romecriteria.org/assets/pdf/19_RomeIII_apA_885-898.pdf. Accessed 8/23/13. 17

IBS-D2

Hard/lumpy stools <25% Loose/watery stools ≥25%

IBS-C, IBS with constipation; IBS-D, IBS with diarrhea; IBS-M, mixed IBS (also referred to as IBS-A [alternating])

1. O’Donnell LJ et al. BMJ. 1990;300:439-440. 2. Longstreth GF et al. Gastroenterology. 2006;130(5):1480-1491.

Type 1Separate

hard lumps, like nuts (hard to pass)

Type 2Sausage-

shaped but lumpy

Type 3Like a

sausage but with

cracks on its surface

Type 4Like a

sausage or snake, smooth and soft

Type 5Soft blobs

with clear-cut edges (passed easily)

Type 6Fluffy

pieces with ragged

edges, a mushy

stool

Type 7Watery,

no solid pieces, entirely liquid

IBS-C2

Hard/lumpy stools ≥25% Loose/watery stools <25%

IBS-M2

Hard/lumpy stools ≥25% Loose/watery stools ≥25%

1 1 1 1 1 1 1

Bristol Stool Form Scale

18

ARS



A. Gluten sensitivity

B. Celiac disease

C. Fibromyalgia

D. A and B

E. B and C

A. B. C. D. E.

0% 0%0%0%0%

6

Which of the following conditions must be considered in the differential diagnosis of IBS-D?

ARS Question 1

Food for Thought…

• What is the diagnostic overlap between celiac disease and IBS-D?

• Who should be tested for comorbid celiac disease?

• What is the role of a gluten-free diet in IBS-D patients who do NOT have celiac disease?

• What is the role of antibiotics for the treatment of IBS-D?

20



CI, confidence interval; OR, odds ratio 1. Ford AC et al. Arch Intern Med. 2009;169(7):651-658. Reprinted from Archives of Internal Medicine April 13, 2009, 169(7). © 2009 American Medical Association. All rights reserved.

Prevalence of Biopsy-Proven Celiac Disease in Patients with IBS-D

Pooled OR for Biopsy-Proven Celiac Disease in Patients Meeting Diagnostic Criteria for IBS vs Controls1

Sanders DS et al. Lancet. 2001;358(9292):1504-1508.

Sanders DS et al. Eur J Gastroenterol Hepatol. 2003;15(4):407-413.

Shahbazkhani B et al. Aliment Pharmacol Ther.2003;18(2):231-235.

Chey WD et al. Gastroenterol. 2007;132(suppl 1):A147.

Ozdil K et al. Dig Dis Sci. 2008;53(7):1852-1855.

Combined (random)

0.2

OR (95% CI)

0.5 1 2 5 10 100 1000

7.29 (1.65, 66.52)

4.49 (0.97, 17.03)

28.23 (1.90, 578.67)

1.52 (0.22, 16.93)

0.67 (0.00, 26.11)

4.34 (1.78, 10.58)

21

Cost-Effectiveness of CS Testing vs Empiric Therapy for IBS-D

$4,023 $4,100

$11,000

$0

$2,000

$4,000

$6,000

$8,000

$10,000

$12,000

Empiric IBS Therapy CS Testing

Cost

IncrementalCost/Effectiveness

CS, celiac sprue

Spiegel BMR et al. Gastroenterology. 2004;126(7):1721-1732.

n/a

• CS testing costs additional $11,000 per additional symptom improvement compared to empiric therapy

• Incremental cost declines rapidly as baseline prevalence of underlying CS increases – Reaches $0.00 when CS prevalence is 8%

22



ACG Recommendations on CS Testing in Patients with IBS-D

• “Routine serologic screening for [CS] should be pursued in patients with IBS-D and IBS-M (Grade 1B)”1

• ACG lists IBS among conditions in which CS occurs more frequently than in the general population and/or for whom GFD may be beneficial2

ACG, American College of Gastroenterology; GFD, gluten-free diet

1. American College of Gastroenterology Task Force on Irritable Bowel Syndrome. Am J Gastroenterol. 2009;104(Suppl 1):S1-S35. 2. Rubio-Tapia A et al. Am J Gastroenterol. 2013;108:656–676. 23

Celiac Prevalence in IBS-D: Overestimated?

Test

Suspected IBS (n=492)

n (%)

Healthy Controls (n=458) n (%) P Value OR (95% CI)

Biopsy-proven celiac disease

2 (0.41) 2 (0.44) NS

Any abnormal celiac disease test

36 (7.32) 22 (4.8) .25 1.49 (0.76, 2.90)

AGA IgG 24 (4.88) 14 (3.06) .70 1.19 (0.50, 2.79)

AGA IgA 8 (1.63) 8 (1.75) .54 1.41 (0.47, 4.22)

EMA 3 (0.61) 2 (0.44) .66 1.65 (0.17, 15.42)

TTG IgA 6 (1.22) 2 (0.44) .15 3.87 (0.61, 24.74)

DQ2 164 (33.33) 180 (39.30) .004 0.61 (0.44, 0.86)

DQ8 81 (16.46) 83 (18.12) .54 1.14 (0.76, 1.70)

Reprinted from Cash BD et al. The prevalence of celiac disease among patients with nonconstipated irritable bowel syndrome is similar to controls. Gastroenterology. 2011;141(4):1187-1193. With permission from Elsevier.

Gluten sensitivity may be more common than biopsy-proven CD compared to controls

24



Nonceliac Patients with IBS-D May Benefit from GFD

• Randomized controlled trials of IBS-D patients without celiac disease randomized to receive either GCD or GFD1,2

Compared with GCD, GFD significantly improved

– Symptom control2 – Bloating2

– Pain2 – Fatigue2

– Stool frequency and consistency2

25 FODMAP, Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyols; GCD, gluten-containing diet

1. Vazquez-Roque MI et al. Gastroenterology. 2013;144(5):903-911. 2. Biesiekierski JR et al. Am J Gastroenterol. 2011;106:508-514.

Dietary Considerations in IBS

1. Somers SC et al. Gastroenterol Clin N Am. 2003;32:507-509. 2. Shepherd SJ et al. Clin Gastroenterol Hepatol. 2008;6:765-771. 3. Shepherd SJ et al. J Am Diet Assoc. 2006;106:1631-1639.

Food intolerances1

26

Lentils, cabbage, Brussels sprouts, asparagus, green beans, legumes

FODMAPs2,3

Sorbitol

Raffinose

Honey, apples, pears, peaches, mangos, fruit juice, dried fruit

Apricots, peaches, artificial sweeteners, artificially sweetened gums

Wheat (large amounts), rye (large amounts), onions, leeks, zucchini

Excess Fructose

Soluble fiber intake1

Fructans

26



Low FODMAP™ Diet: Evolution of Evidence in IBS-D

Double-blind, placebo-controlled rechallenge study*

(N=25)

Fructose and fructans specifically induced symptoms that mimicked IBS-D

Observational cohort studies

Consistent response of 75% of patients across all symptoms

Comparative studies

Low FODMAP vs standard diet associated with significantly better response across all functional GI symptoms

RCTs

(N=30)

2-day intervention of low vs high FODMAP diet; significantly >IBS symptoms with high FODMAP diet

*In response to challenge studies showing that fructose, fructans, sorbitol, mannitol, lactose, fructose, and sorbitol induce symptoms in patients with IBS versus healthy controls

Gibson PR et al. Am J Gasatroenterol. 2012;107:657-666. 27

Low FODMAP ™ Diet in Patients with Gluten Sensitivity

Reprinted from Biesiekierski JR et al. No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates. Gastroenterology. 2013;145:320-328. © 2013 with permission from Elsevier.

Me

an o

vera

ll sy

mp

tom

se

veri

ty s

core

Usual GFD, 7 d Low FODMAP diet added

28



High/Low Gluten Diet: Impact on Symptom Severity

P=.001

P=.016 P=.003

P=.008

No statistically significant changes in abdominal pain, tiredness, or nausea VAS, Visual Analogue Scale Reprinted from Biesiekierski JR et al. No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates. Gastroenterology. 2013;145:320-328. © 2013 with permission from Elsevier. 29

Nocebo response

• Order of dietary interventions associated with degree of symptomatic response

• First intervention significantly induced greater symptomatic changes than subsequent challenges, regardless of what it contained

Global Sx

Pain Bloating Stool

Frequency Stool

Consistency Evidence

Alosetron + + + + 2A/1B

Antidepressants + + 1B

Loperamide + + 2C

Antispasmodics ± + 2C

Probiotics (Bifidobacteria; some combos)

+ 2C

Fiber (psyllium) Insufficient

evidence

Evidence-Based Summary of Medical Therapies for IBS-D Symptoms

Chey WS et al. Gut and Liver. 2011;5:253-266. © 2011 The Korean Society of Gastroenterology, the Korean Society of Gastrointestinal Endoscopy, the Korean Society of Neurogastroenterology and Motility, Korean College of Helicobacter and Upper Gastrointestinal Research, the Korean Association for the Study of Intestinal Diseases, Korean Association for the Study of the Liver and Korean Society of Pancreatobiliary Diseases. Brandt LG et al. Am J Gastroenterol. 2009;104(suppl 1):S1-S35. 30



Rifaximin Significantly Relieves Global Symptoms & Bloating

42.2% 41.6% 32.4% 31.7%

0%

20%

40%

60%

80%

100%

Global symptom improvement Bloating

Systematic Review and Meta-analysis of Rifaximin vs Placebo

Rifaximin

Placebo

*Therapeutic gain=9.8% †Therapeutic gain=9.9%

Menees SB et al. Am J Gastroenterol. 2012;107(1):28-35.

(N=1803)

P<.001 P<.001

* †

31

TARGET 1 and TARGET 2: Loss of Efficacy Over Time

• Two identical phase 3, double-blind, placebo-controlled trials

• Randomized to rifaximin 550 mg or placebo, TID x 2 wk

From N Engl J Med. Pimentel M et al. Rifaximin therapy for patients with irritable bowel syndrome without constipation. Vol 364, p22-32. © 2011 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. 32



Success Rate of Rifaximin Retreatment

33 Pimentel M et al. Dig Dis Sci. 2011;56:2067-2072.

83.5

95.5 94.5

85.4

75

0

10

20

30

40

50

60

70

80

90

100

1st RTX 2nd RTX 3rd RTX 4th RTX 5th RTX

54/65

38/40 17/18

6/7

3/4

Sub

ject

s R

esp

on

din

g, %

PANEL DISCUSSION



THE DIAGNOSTIC DILEMMA OF IBS-C AND CC Brian Lacy, MD

Food for Thought…

• IBS-C and CC: 1 disease or 2?

36



IBS-C & CC

• Classically thought of as 2 separate disorders – Implies that pathophysiology is different

– By extension, if pathophysiology is different, treatments should be different

• Research studies distinguish the 2

• Distinct Rome III definitions

37

Rome III Diagnostic Criterion for IBS*

Recurrent abdominal pain or discomfort† ≥3 d/mo in last 3 mo associated with ≥2 of the following

• Improvement with defecation

• Onset associated with change in frequency of stool

• Onset associated with change in form (appearance) of stool

≥1 of following symptoms ≥25% of occasions for subgroup identification

• Abnormal stool frequency (<3/wk)

• Abnormal stool form (lumpy/hard)

• Abnormal stool passage (straining, incomplete evacuation)

• Bloating/feeling of abdominal distension

• Passage of mucous

• Frequent, loose stools

38

*Criterion fulfilled for ≥3 mo with symptom onset ≥6 mo prior to diagnosis †Discomfort means an uncomfortable sensation not described as pain

Rome Organization. www.romecriteria.org/assets/pdf/19_RomeIII_apA_885-898.pdf. Accessed 8/23/13.



Rome III Diagnostic Criteria for Functional Constipation*

• ≥2 symptoms present ≥25% of the time

• Patients cannot meet criteria for IBS – Straining

– Hard stool or scybala

– Sensation of incomplete evacuation

– Sense of anorectal obstruction/blockade

– Manual maneuvers (digital disimpaction)

– <3 BMs/wk

*Criteria fulfilled for ≥3 mo with symptom onset ≥6 mo prior to diagnosis BM, bowel movement

Rome Organization. www.romecriteria.org/assets/pdf/19_RomeIII_apA_885-898.pdf. Accessed 8/30/13. 39

Pathophysiology of IBS at a Glance

40

Enhanced perception

Altered motility

Visceral hypersensitivity

Food sensitivity/ allergies

Psychosocial factors

SIBO (post- infectious IBS)

Genetic predisposition

5-HT CRF

Adenosine

5-HT, serotonin; CRF, corticotropin-releasing factor; SIBO, small intestinal bacterial overgrowth

Camilleri M et al. Aliment Pharmacol Ther. 1997;11:3-15. Drossman DA et al. Gastroenterology. 2002;123:2108-2131. Lin HC. JAMA. 2004;292:852-858.

Environment Trauma/abuse



Primary Causes of Constipation

Defecation disorders

13%–28%

Functional constipation

(IBS-C and CC)

59%–71%

Slow transit constipation

11%–13%

Schiller LR. Aliment Pharmacol Ther. 2001;15(6):749-763. Mertz H et al. Am J Gastroenterol. 1999;94(3):609-615. 41

IBS & CC: More Than Stool Symptoms

47%

53%

58%

59%

60%

66%

80%

88%

20% 50% 80%

GERD

Constipation

Clothing…

Diarrhea

Fatigue

Trapped gas

Bloating

Abdominal pain

Symptoms in IBS Patients1*

42 *Community survey of >40,000 adults in 8 countries

1. Hungin AP et al. Aliment Pharmacol Ther. 2003;17(5):643-650. 2. Shekhar C et al. Gastroenterology. 2013;145(4):749-757.

5

2.5

2

3

2

1

0

1

0.5

0

Anxiety

Depression

Abdominal pain

Straining

Incompleteevacuation

Symptom Scores in CC Patients vs Healthy Controls2

Healthy controls (n=23)

CC patients (n=11)



In Clinical Practice, IBS-C & CC Often Overlap

43

• Symptom-based criteria for IBS-C and CC overlap

– Abdominal pain/discomfort and gas/bloating creates spectrum between IBS-C and CC

IBS-C

pain/discomfort + gas/bloating - +

Brandt LJ et al. Am J Gastroenterol. 2005;100(suppl 1):S5. Mearin F, Lacy B. Neurogastro Motil. 2012;24(9):791-801.

CC

In Clinical Practice, Patients Move From Group to Group

44

IBS-M1-3

19%–49%

IBS-D1,2

15%–36% IBS-C1-3

19%–44%

Proportions of patients in each subgroup stable over time, but…4:

• 75% will experience change in subgroup over time

1. Simrén M et al. Scand J Gastroenterol. 2001;36(5):545-552. 2. Mearin F et al. Eur J Gastroenterol Hepatol. 2003;15(2):165-172. 3. Tillisch K et al. Am J Gastroenterol. 2005;100(4):896-904. 4. Drossman DA et al. Gastroenterology. 2005;128:580-589.

IBS-M, IBS-mixed (also referred to as IBS-A [alternating])



Food for Thought…

• Does making an accurate diagnosis of IBS-C and CC really matter?

45

Why Distinguish IBS-C from CC?

• Differentiation may help identify distinct comorbid disorders

• An accurate diagnosis may help explain the natural history

• Distinguishing IBS-C from CC may clarify treatment options

46

ARS



A. Comparable incidence of abdominal pain symptoms

B. Similarly delayed colonic transit times

C. Greater visceral sensitivity

D. All of the above

A. B. C. D.

0% 0%0%0%

6

Recent clinical trials show that, compared with patients who have IBS-C, patients with chronic idiopathic constipation have:

ARS Question 2

Inability of Rome Criteria to Distinguish IBS-C from CC

• IBS-C patients had significantly greater frequency of abdominal pain/discomfort – Yet, 44.8% of CC

patients reported experiencing abdominal pain/discomfort within past 3 mo

48

BSI, Brief Symptom Inventory of psychological distress; PAC-QOL, Patient Assessment of Constipation Quality of Life

Wong et al. Am J Gastroenterol. 2010;105:2228-2234.

21 180 231

IBS-C (n=201) CC (n=411)

Overlap between IBS-C and CC when Rome III requirement that CC cannot be

diagnosed in a patient who meets criteria for IBS is suspended



Patients with IBS-C & CC vs HVs

• If the Rome III requirement that patients meeting criteria for IBS cannot be diagnosed with CC was suspended, 86% (20 of 23) of IBS-C patients would meet criteria for CC – Similarly delayed colonic and

right segmental transit vs HVs

– Significantly increased abdominal and BM symptoms vs HVs

49 HV, healthy volunteer

Shekhar C et al. Gastroenterology. 2013;145(4):749-757.

Patient Group Transit Times (mean; range)

Colonic transit times (P<.001)

HV 38 h; 6-66 h

IBS-C 64 h; 24-72 h

CC 71 h; 13-72 h

Right colonic transit times (P<.001)

HV 5 h; 0-25 h

IBS-C 17 h; 3-35 h

CC 21 h; 8-51 h

Patients with IBS-C & CC vs HVs: Sensory Thresholds

12.3

25.9 29.6

12.5

21.3 23.4

15.6

26.6 32.7

0

10

20

30

40

First sensation Stool sensation Pain threshold

Sensory Thresholds, mm Hg

HV (n=23)

IBS-C (n=23)

CC (n=11)

*Compared with CC patients, P<.05 Shekhar C et al. Gastroenterology. 2013;145(4):749-757.

• IBS-C patients tend to reside at sensitive end of visceral sensitivity spectrum vs CC patients – Hypersensitivity: 30% vs 0%, respectively

– Hyposensitivity: 4% vs 27%, respectively

P=.10

P=.10 P=.01

*

50



The Bottom Line: Treat the Predominant Symptom

• CC: constipation

• IBS-C: abdominal pain or constipation or gas/bloating

• Recognize that patients will shift groups over time – Should not be considered a warning sign

– It’s the natural history and is expected

• Therefore, treatments will need to shift over time

51

Summary

• Use Rome III criteria as diagnostic tool

• IBS-C and CC exist on a continuum – They don’t exist in isolation

• Expect movement between groups

• Treat the predominant symptom

52



PANEL DISCUSSION

NUANCED TREATMENT OF IBS-C AND CC

Amy E. Foxx-Orenstein, DO, FACG, FACP

ARS



A. Cognitive behavioral therapy

B. Hypnotherapy

C. Acupuncture

D. A and B

E. A, B, and C

A. B. C. D. E.

0% 0%0%0%0%

6

Which of the following psychological treatment(s) has/have been shown to improve symptoms of IBS?

ARS Question 3

Biofeedback in IBS-C

• Prospective study in patients with dyssynergic defecation (N=50) plus IBS-C (n=29) – Similar responses to biofeedback in dyssynergic and

IBS-C groups (55% vs 67%, P >0.05)

– IBS-C symptoms disappeared in 41% patients who had pre-treatment IBS-C symptoms • Symptom resolution more common in biofeedback

responders vs nonresponders (P<.05)

• Conclusion: assessment of pelvic floor function (and therapy to address it) may be useful in select patients with IBS-C

Patcharatrakul T et al. J Clin Gastroenterol. 2011;45:593–598. 56



Other Mind-Body Therapies That Significantly Improve IBS

• Improves GI symptoms, psychological distress, QoL1-3

CBT

• Reduces overall IBS severity at 3 mo4

Mindfulness Training

• Improves IBS vs usual care (49% vs 28%); 20 studies, N=12785

Psychological Therapy

• Reduces symptoms of moderate-to-severe and refractory IBS6-8

Hypnotherapy

• Improves symptom severity; less likely to have symptoms worsen9

Exercise

57

1. Lackner JM et al. Clin Gastroenterol Hepatol. 2008;6(8):899-906. 2. Lackner JM et al. Clin Gastroenterol Hepatol. 2010; 8(5):426-32. 3. Drossman DA et al. Gastroenterology. 2003;125(1):19-31. 4. Gaylord SA et al. Am J Gastroenterol. 2011;106(9):1678-1688. 5. Ford AC et al. Gut. 2009;58(3):367-378. 6. Halland M et al. Nat Rev Gastroenterol Hepatol. 2013;10:13–23. 7. Miller V et al. Gastroenterology. 2012;142(Suppl 1):S-29635. 8. Lindfors P et al. Am J Gastroenterol. 2012;107:276–285. 9. Johannesson E et al. Am J Gastroenterol. 2011;106:915–922.

CC Therapies: Graded Recommendations

Level A

Bisacodyl

Lactulose

Lubiprostone

PEG

Psyllium

Senna

PEG, polyethylene glycol; RCT, randomized controlled trial Note: Linaclotide was not included in this review

Leung L et al. J Am Board Fam Med. 2011;24:436-451. 58

Level B

Bran

Docusate sodium

Methylcellulose

Polycarbophil

Sorbitol

Level C

Milk of magnesia



Food for Thought…

• Are all fiber products equal in reducing symptoms of IBS-C and CC?

59

Overall Forest Plot of Fiber Studies

Random Treatment

n/N Control

n/N RR (random)

95% CI Weight

% RR (random)

95% CI

Bran (subtotal)

114 107 31.75 1.02

(0.82, 1.27)

Ispaghula (subtotal)

161 160 65.24 0.78

(0.63, 0.96)

Fiber* (subtotal)

25 24 3.00 1.37

(0.62, 3.01)

Total 300 291 100.00 0.87

(0.76, 1.00)

0.1 0.2 0.5 1 2 5

Favors treatment Favors control

10

*Unspecified

Ford AC et al. BMJ. 2008; 337;a2313. 60



Psyllium vs Bran vs Placebo for IBS-C

57 59

46

40

51

57

35

41

32

0

10

20

30

40

50

60

70

Month 1 Month 2 Month 3

Psyllium

Bran

Placebo

*Adequate symptom relief for ≥2 of previous 4 wk Bijkerk CJ et al. BMJ. 2009;339:b3154.

Re

spo

nd

ers

, %*

61

PEG 3350 & Electrolytes for IBS-C

• RCT of PEG 3350 + E (n=68) vs placebo (n=71)

• Primary endpoint – No. SBMs/d in Wk 4

• PEG 3350 + E significantly improved no. SBMs/d, stool consistency, and straining vs placebo (P<.0001) – PEG 3350 + E significantly

improved abdominal pain from baseline (P<.005)

– Not observed with placebo

1.28

4.4

1.37

3.11

Baseline Wk 4

No. SBMs (weekly mean)

PEG 3350 + E Placebo

SBM, spontaneous bowel movement Chapman RW et al. Am J Gastroenterol. 2013;108:1508-1515.

P<.0001

62



Sodium Picosulfate for CC

Baseline 4 Wk

SPS 0.9 ± 0.1 3.4 ± 0.2

Placebo 1.1 ± 0.1 1.7 ± 0.1

P value — P<.0001

• Patients with CC (N=367) randomized to SPS or placebo

• Primary outcome: – Mean complete SBMs/wk over 4 wk

• Overall PAC-QoL score improved

• Conclusion: SPS effective, safe, well-tolerated in CC

PAC-QoL, Patient Assessment of Constipation Quality of Life; SPS, sodium picosulfate

Mueller-Lissner S et al. Am J Gastroenterol. 2010;105(4):897-903. 63

ARS

A. Lubiprostone

B. Linaclotide

C. PEG 3350

D. All of the above are indicated for both IBS-C and chronic idiopathic constipation

A. B. C. D.

0% 0%0%0%

6

Which of the following does not have a specific indication for IBS-C and chronic idiopathic constipation?

ARS Question 4



Food for Thought…

• What is the role of medical therapy in treating patients with IBS-C and CC?

65

Global Symptoms

Abdominal Pain Bloating

Stool Frequency

Stool Consistency

Antidepressants (SSRIs, TCAs)

+ +

Fiber (psyllium) + +

Laxatives (PEG) +

Lubiprostone + + +

Linaclotide + + + + +

Evidence-Based Summary of Medical Therapies for IBS-C & CC Symptoms

Chey WS et al. Gut and Liver. 2011;5:253-266. 2011 © Copyright by Gut and Liver. All rights reserved. Brandt LG et al, for the ACG Task Force on IBS. Am J Gastroenterol. 2009;104(suppl 1):S1-S35. 66



Lubiprostone for IBS-C: Data from Two Phase 3 Trials

17.9%

10.1%

0%

3%

6%

9%

12%

15%

18%

21%

Combined OverallResponders, %

Lubiprostone8 mcg BIDn=780

Placebon=387

• 12-wk treatment period

• Overall responder = monthly responder ≥2-3 mo

• Monthly responder = at least moderate relief 2-4 wk or significant relief >2-4 wk

Drossman DA et al. Aliment Pharmacol Ther. 2009;29:329-341.

P=.0001

67

Long-term Efficacy of Lubiprostone: Monthly Responder Rates

68 Chey WD et al. Aliment Pharmacol Ther. 2012;35:587-599. Reproduced with permission of Blackwell Publishing Ltd.

N=476 patients with IBS-C Open-label lubiprostone, 8 μg BID x36 wk



Total Elderly >65 Total 0

5

10

15

20

25

30

35

Nau

sea

inci

de

nce

, %

Reproduced from Saad R, Chey WD. Exp Review Gastroenterol Hepatol. 2008;2(4):497-508. With permission of Expert Reviews Ltd.

Phase 2 + 3 Trials in CC 24-mcg BID

Phase 3 Trials in CC + IBS-C 8-mcg BID

102

Incidence of Nausea with Lubiprostone

• CC: 24 mcg BID with food

• IBS-C: 8 mcg BID with food

69

Linaclotide for IBS-C: Adequate Symptom Relief ≥13/26 Wk

49.1%

25.1%

0%

10%

20%

30%

40%

50%

60%

Linaclotide 290 mcg (n=401) Placebo (n=403)

Adequate Relief: IBS Symptoms, %

Chey WD et al. Am J Gastroenterol. 2012;107:1702-1712.

P<.0001 NNT=4.2

Most common AE: diarrhea (19.7% vs 2.5%)

70



% Change, Worst Abdominal Pain Over 26 Wk

ANCOVA, analysis of covariance Chey WD et al. Am J Gastroenterol. 2012;107:1702-1712. Reproduced with permission of Blackwell Publishing Ltd.

Linaclotide Phase 3 IBS-C Trial: Abdominal Pain

71

Symbiotic for CC

5

6.1

0

1

2

3

4

5

6

7

No. BMs/wk(N=266)

Control

Symbiotic

• 14-day crossover trial of each:

– Symbiotic: yogurt with 10(8) UFC/g of B animalis and fructoligosaccharide

– Control: lacteous dessert without probiotics

• Symbiotic significantly improved stool frequency, stool consistency, straining, and pain with defecation

DePaula JA et al. Acta Gastroenterol Latinoam. 2008;38(1):16-25.

P<.01

72



Food for Thought…

• What IBS-C and CC treatments are on the horizon?

73

Emerging Therapies

• Prucalopride – 5-HT4 receptor agonist

• Chenodeoxycholate – Primary bile acid synthesized from cholesterol

• Elobixibat – First-in-class ileal bile acid

74



Summary

• Range of prescription and nonprescription treatments of IBS-C and CC

• High degree of interpatient variability – Evaluation and treatment is tailored to subtype and to

individual patient

• Trials of treatments singly or in combination may be necessary to identify regimens that provide maximum efficacy and minimal side effects

• Physician–patient relationship is key

75

PANEL DISCUSSION



SHARED DECISION-MAKING TO IMPROVE CARE

William D. Chey, MD

Clinician/Patient Disconnect? I can’t deal with the straining and hard stools anymore…

Constipated?? She is moving her

bowels every day…

78



What Do Patients Want? (Expectations vs Reality)

0

20

40

60

80

100

120 Expected, %

Provided, %

Halpert A et al. Dig Dis Sci. 2010;55(2):375-383.

The ideal office visit provides an accepting and supportive environment

N=1028

79

ARS

A. Establish a strong and positive physician-patient relationship

B. Assess severity and treat the predominant symptom

C. Perform a thorough work-up including imaging tests to confirm diagnosis

D. A and B

E. B and C

A. B. C. D. E.

0% 0%0%0%0%

6

Which of the following are important strategies for improving the care of patients with IBS-C or CC?

ARS Question 5



Improving Communication & Care

• Empathic listening, explanations, and reassurance

• Make sure you understand the symptoms

• Get a feel for the patient’s QoL

• Emphasize the basics (diet, sleep, exercise)

• Assess severity and treat predominant symptom(s)

• Set follow-up

• Create a healthcare team: nurse, physician assistant, dietician, psychologist, psychotherapist

• Provide educational materials or give out online resource sites (ACG + AGA websites: www.iffgd.org, www.ibsgroup.org)

83 81

PANEL DISCUSSION



THANK YOU!

WELCOME & INTRODUCTIONS · •Formulate individualized treatment plans for patients with IBS...

Documents

Transcript of WELCOME & INTRODUCTIONS · •Formulate individualized treatment plans for patients with IBS...